Considerable evidence has linked mitochondrial dysfunction to the process of neurodegeneration. Parkinson's disease (PD) involves a specific mitochondrial defect centering around complex I of the electron transport chain-the target enzyme of the parkinsonism inducing neurotoxin, MPTP. This defect appears to be genetic, arising from the mitochondrial rather than nuclear genome since expression of PD mitochondrial DNA (mtDNA) in human cell lines lacking endogenous mtDNA results in creation of the complex I defect and several other pathogenic features including endogenous mtDNA results in creation of the complex I defect and several other pathogenic features including production of oxygen radicals, sensitization toward apoptotic toxins, disordered calcium metabolism, elevations of oxygen radical defense enzymes, and ultrastructural changes, Defects in PD mtDNA may be critically important in PD pathogenesis. A definitive study of potential sequence changes has never been accomplished. Using recently developed high speed DNA sequencing methods, we will conduct an exhaustive search of the entire mitochondrial genome of PD patients and controls in both brain and blood. Success should result in identification of genetic factors critical to the pathogenesis of PD and provide a basis for study of similar disorders where mtDNA may be pathogenic.